ABSTRACT Sepsis is a major cause of mortality worldwide. Approximately 250,000 sepsis-resulted deaths occur each year in the United States alone. In spite of vigorous research, molecular understanding of this systemic inflammatory response syndrome is not complete. A common type of sepsis results from lipopolysaccharide (LPS) intoxication from Gram-negative bacterial infection. The latest genetic analyses on LPS resistance in mice reveal the critical role of Glucocorticoid-Induced Leucine Zipper (GILZ) in protection against LPS-induced sepsis. We recently discovered that acute ethanol exposure upregulates GILZ expression, and protects mice from LPS septic shock. Moreover, research by others indicates that isopropanol protects mice from Staphylococcal enterotoxin B-induced septic shock. These findings prompt us to seek the potential link between alcohol activation of the GILZ gene and alcohol attenuation of the sepsis induced by LPS and SEB. The overall hypothesis is that GILZ in marrow-derived immune cells is pivotal to alcohol protection against sepsis induced by bacterial toxins, and the short-chain alcohols that are structurally close to ethanol share the same mechanism for immunosuppression. Two specific aims are proposed for this R21 application: 1) to test the hypothesis that GILZ depletion in marrow-derived immune cells abrogates ethanol protection against septic shock induced by LPS and SEB; 2) to examine the prediction that the short-chain alcohols which are structurally close to ethanol share the same properties of upregulating GILZ expression and protecting against septic shock induced by LPS and SEB. Completion of this project will determine whether GILZ is a key regulator controlling the host immune response to the bacterial toxins. Molecular understanding of this mechanism will define new therapeutic targets for better intervention of sepsis.